Structural analysis of trimeric phospholipase A(2) neurotoxin from the Australian taipan snake venom.

MedLine Citation:

PMID:
22776098
Owner:
NLM
Status:
Publisher

Abstract/OtherAbstract:

Snake pre-synaptic neurotoxins endowed with phospholipase A(2) activity (SPANs) are potent inducers of paralysis through specific disruption of the neuromuscular junction pre-synaptic membrane and represent a valuable tool for investigating neuronal degeneration and recovery. They have different structural complexity and a wide range of lethal potency and enzymatic activity, but share similar mechanism of action. Whilst no correlation has been reported between neurotoxicity and enzymatic activity, toxicity increases with structural complexity and phospholipase A(2) oligomers show 10-fold lower LD(50) values when compared to their monomeric counterparts. Up to date, no structural study has been done on multimeric SPANs to shed light on the correlation between structural complexity and neurotoxicity. In this study we investigated the structure of taipoxin, a trimeric phospholipase A(2) neurotoxin, and of its subunits by X-ray crystallography and small angle X-ray scattering analysis. We present here the high-resolution structure of two isoforms of taipoxin β subunit, which show no neurotoxic activity but enhance the activity of the other subunits in the complex. One isoform shows no structural change that could justify the lack of activity. The other displays three point mutations in critical positions for the catalytic activity. Moreover, we designed a model for the quaternary structure of taipoxin under physiological conditions, in which the three subunits are organized into a flat holotoxin with the substrate binding sockets exposed on the same side of the complex, suggesting a role for this interface in the toxin-membrane interaction.